Intermediate steroid compounds

ABSTRACT

A novel process for the preparation of oxoetiocholenic acid of the formula ##STR1## and intermediates therefore.

PRIOR APPLICATIONS

This application is a division of U.S. patent application Ser. No.08/964,836 filed Nov. 5, 1997, which is a division of U.S. patentapplication Ser. No. 08/758,951 filed Dec. 2, 1996, now U.S. Pat. No.5,770,748, which is a division of U.S. patent application Ser. No.08/519,772 filed Aug. 28, 1995, now U.S. Pat. No. 5,650,526.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a novel process for thepreparation of oxoetiocholenic acid and novel intermediates therefore.

These and other objects and advantages of the invention will becomeobvious form the following detailed description.

THE INVENTION

The novel process of the invention of oxoetiocholenic acid of theformula ##STR2## comprises reacting a compound of the formula ##STR3##wherein the A and B rings are selected from the group consisting of##STR4## K is an oxo protective group selected from the group consistingof ##STR5## wherein n is 2 or 3, and R₁ is an ether or ester with ahalonitrile in the presence of a base to obtain a compound of formula##STR6## wherein rings A and B have the above definition and the wavylines indicate a mixture of isomers, reacting the latter to free the3-ketone to obtain a compound of the formula ##STR7## wherein the wavylines have the above meaning, reacting the latter with an acid of theformula HX in which X is halogen in an anhydrous medium to obtain acompound of the formula ##STR8## in which X and the wavy lines have theabove meaning, protecting the hydroxy in the form of an ester to obtaina compound of the formula ##STR9## wherein Z is a protective ester groupof the hydroxy and X and the wavy lines have the above meaning,subjecting the latter to the action of a dehyprohalogenation agent toobtain the compound of the formula ##STR10## wherein Z and the wavylines have the above meaning, subjecting the latter to an alkalinehydrolysis, then to an acid treatment to obtain the compound of formulaI.

Examples of R₁ as an ether are alkyl of 1 to 6 carbon atoms,alkoxyalkoxyalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atomsor aralkyl of 7 to 12 carbon atoms.

When R₁ is alkyl, it is preferably methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, pentyl or hexyl. When R₁ isalkoxyalkoxyalkyl, it is preferably methoxyethoxymethyl and when R₁ isaralkyl, it is for example benzyl or phenethyl. When R₁ is aryl, it ispreferably phenyl or phenyl substituted by one or more alkyls.

When R₁ is an ether, it can also be a silylated group such astrialkylsilyl like trimethylsilyl, tert-butyldimethylsilyl or atriarylsilyl such as triphenylsilyl or diarylalkylsilyl such as diphenyltert-butylsilyl.

When R₁ forms an ester, it can be any ester group known to one skilledin the art for blocking the 3- position in this form and particularly itcan be --COR₁, R₁ being alkyl, aryl or aralkyl as defined above.

A particular subject of the invention is a process as defined previouslycharacterized in that a starting compound of formula II is used in whichrings A and B are ##STR11## wherein R₁ is defined as previously andparticularly alkyl of 1 to 6 carbon atoms.

The halonitrile which is reacted with the compound of formula II can bebromoacetonitrile or preferably chloroacetonitrile. The operation iscarried out in the presence of a strong base, preferablynon-nucleophilic, such as an alcoholate, a hydride, an amide or ahydroxide of an alkali metal, or an organolithium compound such as themethylate, the ethylate, the terbutylate or the teramylate of sodium orpotassium, lithium diisopropylamide, or also sodium hydroxide orpotassium hydroxide.

It may be advantageous to operate in hydrogeneous phases in the presenceof a phase transfer catalyst which can be a quaternary ammonium saltsuch as tetrabutylammonium bromide, triethylbenzyl-ammonium chloride ortricaprylmethylammonium chloride, or a phosphonium salt. An alcoholateis preferably used such as the terbutylate or teramylate of potassium orsodium.

The reaction is carried out in an organic solvent such as toluene,dichloromethane, dimethoxyethane, dimethylformamide, tetrahydrofuran ora mixture of these solvents, for example a toluene/tetrahydrofuranmixture or a terbutanol/tetrahydrofuran mixture.

The release of the 3-ketone function is carried out by means appropriateto the nature of the protective group. An acid agent is used in thepresence of water or a water-alkanol mixture in the case of a ketal. Itis for example a mineral or organic acid such as hydrochloric acid,hydrobromic acid, sulfuric acid, perchloric acid, nitric acid, p-toluenesulfonic acid, acetic acid, formic acid, oxalic acid or a mixture ofacids, or also an acid resin, for example a sulfonic acid resin. In thecase of a thioketal or a mixed ketal, the deprotection of the 3-oxo iscarried out by the action of iodine in the presence of a base such as analkali metal bicarbonate, or by the action of iodine in catalyticquantity in the presence of an oxidizing agent, particularly hydrogenperoxide, by the action of methyl iodide, glyoxylic acid, or also saltsof metals such as mercury or cadmium. The operation can generally becarried out in a solvent such as a lower alkanol, for example methanolor ethanol, mixed with a halogenated solvent, for example methylenechloride in the presence of water. In the case of a mixed ketal, thedeprotection is also carried out for example by a mercuric salt such asmercuric chloride in the presence of an acetic acid/potassium acetatebuffer at about 100° C., by Raney nickel under the same conditions asabove or by a hot hydrochloric acid--acetic acid mixture.

In the case where R₁ is an ether or ester, an acid treatment is alsoused under the conditions described above for the ketal. There can beused for example acetic acid or sulfuric acid or a mixture of theseacids.

The HX which is used for opening the epoxide function can be for examplehydrobromic acid or, preferably, hydrochloric acid. The reaction ispreferably carried out in an anhydrous medium in an organic solvent,preferably only slightly polar or non-polar, such as dimethoxyethane,ethyl ether, ethyl acetate, dichloromethane or toluene, these last twobeing preferred. The operation is advantageously carried out in thepresence of a tertiary amine such as pyridine or triethylamine.

The protection of the 20-hydroxy function in the form of an ester can becarried out by the usual methods using a carboxylic acid derivative andin particularly a halide or an anhydride of an alkanoic or aromaticacid, preferably in the presence of a nitrogenous base. There can beused for example acetic acid, propionic acid, valeric acid or benzoicacid anhydride in the presence of pyridine.

The dehydrohalogenation is carried out by the action of a base such as atertiary amine such as triethylamine or pyridine, or of anon-nucleophilic base such as lithium carbonate--lithium bromide, sodiumhydroxide or potassium hydroxide. The reaction is carried out in anon-hydrophilic organic solvent such as dichloromethane,dimethylformamide, dimethylsulfoxide or, preferably, toluene. Theoperation is advantageously carried out at reflux of the reactionmedium.

The alkaline hydrolysis is carried out using a strong base, particularlybarium hydroxide, potassium hydroxide, sodium carbonate, or preferablysodium hydroxide. The operation is carried out in the presence of wateror a water--alcohol mixture which stabilizes the basic salt formed, ifappropriate in a double-phase system, with the solvent in which thepreceding stage has been carried out.

Isolation of oxoetiocholenic acid is carried out by acid treatment ofthe basic salt by the usual methods, for example using a mineral acidsuch as sulfuric acid or hydrochloric acid.

A particular subject of the invention is a process as definedpreviously, characterized in that the operation is carried out withoutintermediately isolating the compounds of formula IV and the subsequentcompounds.

Also a subject of the invention as new intermediates for the process ofthe invention are compounds of the formula ##STR12## in which rings A1and B1 have the meaning indicated for rings A and B, or ##STR13## andthe wavy lines have the above meaning, the compounds of the formula##STR14## in which X and the wavy lines have the meaning indicatedpreviously and Z' is hydrogen or a protective ester group of the hydroxyand the compounds of the formula ##STR15## in which Z and the wavy lineshave the above meaning.

The compound of formula II is described in French Patent 1,563,607.

The acid of formula I or oxoetiocholenic acid is a product knownparticularly as a synthesis intermediate and described, for example, inEuropean Application 562,849.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLES Example 1

17β-Δ⁴ -androstene-3-one: oxoetiocholenic acid

STAGE A: 17,20-epoxy-3-methoxy-17α-Δ³,5 -preg nadiene-21-nitrile

15 g of 3-methoxy-Δ³,5 -androstadiene-17-one in 120 ml oftetrahydrofuran and 5.5 g of terbutanol were cooled to -45° C. under aninert gas atmosphere and then 9 g of potassium terbutylate were added.Then, over 4 hours at about -45° C., 4.8 g of chloroacetonitriledissolved in 30 ml of tetrahydrofuran were added. The reaction mixturewas introduced under an inert gas atmosphere into a solution cooled to0° C. of 2 g of ammonium chloride in 300 ml of water. Then, the mixturewas maintained with stirring for 30 minutes. It was filtered, washedwith methanol with 20% water and the residue was taken up in 15 ml of an1-2 isopropanol/isopropyl ether mixture, followed by separating andwashing again with 30 ml of the above mixture. After separation anddrying under reduced pressure, 13.4 g of the expected product melting at180° C. were obtained.

IR spectrum (CHCl₃)

    ______________________________________    conj. C═C      1654-1629 cm.sup.-1    C═N            2248 cm.sup.-1    ______________________________________

NNR spectrum (CDCl₃ ppm)

    ______________________________________    0.94              CH.sub.3 in position 18    0.98              CH.sub.3 in position 19    3.49              CH in position 20    3.58              CH.sub.3 in position 3    5.14 (d)          CH in position 4    5.25 (d)          CH in position 6    ______________________________________

STAGE B: 17β-carboxy-Δ⁴ -androstene-3-one: oxoetiocholenic acid

1) Hydrolysis of the enol ether in position 3

64 ml of acetic acid, 13 ml of water and 13 ml of dilute sulfuric acid(2N) were added under an inert atmosphere to 12.85 g of17,20-epoxy-3-methoxy-17α-Δ³,5 -pregnadiene-21-nitrile prepared in StageA. The reaction mixture was stirred for 90 minutes at ambienttemperature and 64 ml of toluene and 64 ml of water were added over 10minutes, followed by decanting. The toluene phase was washed with water,then with a 2% aqueous solution of sodium bicarbonate, and the toluenewas distilled off under 150/100 mbars until a volume of about 25 ml wasobtained.

2) Opening of the epoxide

100 ml of dichloromethane and 6 ml of pyridine were added under an inertatmosphere to the above reaction medium, followed by cooling to -5° C.Gaseous hydrochloric acid was introduced over about 3 hours and themixture was stirred for one hour at -5° C. The excess hydrochloric acidwas neutralized by addition of 21.5 ml of pyridine.

3) Acetylation of the chlorhydrin

The temperature of the above suspension was allowed to return to about+10° C. and then over 30 minutes, 7.8 ml of acetic anhydride and 6 ml ofpyridine were added. The reaction mixture was stirred for 16 hours atambient temperature, followed by washing with water and decanting. Theresidue was distilled under 400 to 150 mbars until a crystallized crudeproduct was obtained.

4) 17-20 elimination of the acetate derivative

50 ml of toluene and 25 ml of triethylamine were added under an inertatmosphere to the above product and the mixture was refluxed for 3 hoursand 30 minutes and then allowed to return to ambient temperature.

5) Hydrolysis of the enol acetate

50 ml of water and 25 ml of sodium hydroxide were added under an inertatmosphere to the reaction medium prepared previously and the mixturewas stirred for 20 hours. 250 ml of water were added and the aqueousphase was decanted.

6) Acidification of the sodium salt/preparation of the acid

The aqueous phase was cooled to +10°/+15° C. under a nitrogen atmosphereand 80 ml of dilute sulfuric acid (4N) were added with stirring. Thegaseous hydrocyanic acid was driven off by sweeping with an inert gasand the precipitate formed was filtered off, washed with water and driedunder reduced pressure to obtain 9.33 g of the expected product meltingat 255-256° C.

IR spectrum (CHCl₃)

    ______________________________________    C═O            1702 cm.sup.-1    Δ.sub.4 -3-one                       1662-1615 cm.sup.-1    ______________________________________

NNR spectrum (CDCl₃ ppm)

    ______________________________________    0.79              CH.sub.3 in position 18    1.19              CH.sub.3 in position 19    5.74              CH in position 4    ______________________________________

Example 2

17β-carboxy-Δ⁴ -androstene-3-one: oxoetiocholenic acid

STAGE A: 17,20-epoxy-17α-Δ⁴ -pregnene-3-one-21-nitrile

1.017 g of the product obtained in Stage A of Example 1 were mixed for 3hours at 20° C. under an inert gas atmosphere with 10 ml of acetic acidand 5 ml of water and 4 ml of tetrahydrofuran were added. The mixturewas stirred for 2 hours and the solvents were evaporated off underreduced pressure. The residue was chromatographed on silica (eluant:toluene--ethyl acetate 8-2) to obtain 691 mg of the expected product.

IR spectrum (CHCl₃)

    ______________________________________           C═N      2240 cm.sup.-1           C═O      1662 cm.sup.-1           C═C      1617 cm.sup.-1    ______________________________________

NMR scectrum (CDCl₃ ppm)

    ______________________________________    0.95              CH.sub.3 in position 18    1.20              CH.sub.3 in position 19    3.32-3.48         CH in position 20    5.75              CH in position 4.    ______________________________________

STAGE B1: 17α-chloro-Δ⁴ -pregnene-3-oxo-20-ol-21-nitrile

1 g of the product of Stage A was added to 2 ml of a 4.7N solution ofgaseous hydrochloric acid in 4.7N solution of gaseous hydrochloric acidin 4.7N dimethoxyethane cooled to +5°/+10° C. and the mixture wasstirred for 3 hours. A further 1 ml of reagent was added, followed bystirring for one hour while maintaining the temperature at 10° C. andthe reaction mixture was used as is for the following stage.

STAGE B2: 17α-chloro-20-acetoxy-Δ⁴ -pregnene-3-one-21-nitrile

0.25 g of the epoxide of Stage A dissolved in 10 ml of dichloromethaneand 0.1 ml of pyridine was stirred under an inert atmosphere. A currentof gaseous hydrochloric acid was introduced slowly at about 20° C. forone hour and the excess hydrochloric acid was eliminated by sweepingwith an inert gas. Half of the reaction medium was used as is forfollowing stage and the other half was washed with water and dried. Thesolvent was evaporated under reduced pressure and the residue was takenup in 2 ml of an ethanol--water mixture (1-1), followed by triturating,separating, washing with water and drying under reduced pressure toobtain 0.1 g of the expected product melting at 230°-240° C. (decomp.).

NMR spectrum (CDCl₃ ppm)

    ______________________________________    0.97-0.98         CH.sub.3 in position 18    1.21              CH.sub.3 in position 19    3.05-3.22         OH in position 20    4.56-4.77         CH in position 20    ______________________________________

STAGE C: 20-acetoxy-17α-chloro-Δ⁴ -pregnene-3-one-21-nitrile

3 ml of dimethoxyethane were added to the reaction medium of Stage B1cooled to 10° C. and then 1.7 ml of pyridine and 1 ml of aceticanhydride were added over a few minutes. The reaction medium was allowedto return to ambient temperature over one hour and 0.8 ml of pyridineand 5 ml of water were added. The mixture stood at +4° C. for 16 hoursand the precipitate formed was separated off, washed withdimethoxyethane and dried under reduced pressure to obtain 0.364 g ofthe expected product melting at 238° C.

IR spectrum (CHCl₃)

    ______________________________________    OAc                1757 cm.sup.-1    Δ.sup.4 -3-one                       1665-1616 cm.sup.-1    ______________________________________

NMR spectrum (CDCl₃ ppm)

    ______________________________________    1.04            CH.sub.3 in position 18    1.21            CH.sub.3 in position 19    2.22            O--Ac    5.74            CH in position 4 and in                    position 20.    ______________________________________

STAGE D; (E+Z) 20-acetoxy-Δ⁴,17(20) -pregnadiene-3-one-21-nitrile

0.5 ml of toluene and 0.2 ml of triethylamine were added to 100 mg ofthe product obtained of Stage C under an inert atmosphere. The mixturewas refluxed for 5 hours, then cooled to 10° C. The precipitate wasseparated off, washed with toluene, then with water and dried underreduced pressure to obtain 91 mg of the expected product melting at185-190° C.

IR spectrum (CHCl₃)

    ______________________________________    C.tbd.N (conj)     2223 cm.sup.-1    OAc                1773 cm.sup.-1    Δ.sup.4 -3-one                       1662-1616 cm.sup.-1    ______________________________________

NMR spectrum (CDCl₃ ppm)

    ______________________________________    0.97              CH.sub.3 in position 18    1.19              CH.sub.3 in position 19    2.20              O--Ac    5.74              CH.sub.3 in position 4.    ______________________________________

STAGE E: 17β-carboxy-Δ⁴ -androstene-3-one: oxoetiocholenic acid

using the procedure of Stages B5 and B6 of Example 1, the productobtained in Stage D was reacted to obtain the expected oxoetiocholenicacid.

Various modifications of the process of the invention may be nadewithout departing from the spirit or scope thereof and it is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

What we claim is:
 1. A compound having a formula the group consisting of ##STR16## wherein X is halogen, Z' is hydrogen or a hydroxy protective group and the wavy lines indicate a mixture of isomers. 